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The role of diet and gastrointestinal microbes in animal ageing and metabolism

饮食和胃肠道微生物在动物衰老和代谢中的作用

基本信息

批准号：
BB/H01974X/1
负责人：
David Weinkove
金额：
$ 43.99万
依托单位：
Durham University
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2010
资助国家：
英国
起止时间：
2010 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FH01974X%2F1
关键词：
role diet gastrointestinal microbes animal

项目摘要

There is much evidence that in general, diet affects ageing. Diet also impacts many major diseases and there is a multibillion-dollar industry that produces dietary supplements with the goal of improving human health. There are a vast number of constituents of the human diet, so assessing the effect of each them on ageing is a monumental task. Studying ageing in laboratory animals allows for quicker and better-controlled experiments. The tiny nematode worm, Caenorhabditis elegans, with a lifespan of only a few weeks, is a well-established lab animal for investigating the biology of ageing. The lifespan of the worm can be extended considerably by the disruption of some genes in the worm, several of which have clear human counterparts. For example disruption of genes similar to those needed to respond to insulin in humans, causes the worm to live longer. Experiments in mice have shown that this finding is also relevant to mammals. The digestive tracts of animals are populated by numerous microbes, mainly bacteria and these microbes assist nutrition in many ways. As well as assisting uptake of nutrients, gut bacteria produce compounds such as essential amino acids and vitamins that can't be made by the animal host. It has been suggested that changes in gut microbes can cause obesity. In the lab we maintain C. elegans on a single species of live bacteria, a harmless strain of E. coli, derived from the human intestine. This strain provides food but needs to be alive to provide good nutrition. We have discovered a mutant strain of E. coli, which when fed to worms makes them live considerably longer. We have found that the reason why this mutant causes the animals to live longer is a decrease in the synthesis of folic acid. Folic acid is needed in all cells for a variety of purposes, especially for cell growth, but folic acid is only made in microbes and plants so animals have to rely on their diet. Our experiments show that the lifespan of the worms eating the mutant bacteria is extended because they are receiving less folic acid than worms on the normal bacteria. In addition, the fact that the bacteria have less folic acid to support their own metabolism also contributes to the slowed ageing of the worms that eat them. We don't yet understand how reduced folic acid causes this effect but we know that is not because extra folic acid is toxic. E. coli is probably the best studied organism there is, because for over 60 years it has been used to understand the basic workings and metabolism of cells. E. coli has around 4000 genes and there is a collection of 3909 strains in which a single gene has been disrupted from each strain in the collection. The aim of this proposal is to feed worms on each of these mutant strains and look for long-lived worms and worms that grow slowly. We expect to find several E. coli mutants that increase worm lifespan and/or affect nutrition. Firstly, we should find mutants that disrupt genes related to folic acid metabolism. The identity of these genes will help us understand how the folic acid effect works. Secondly, we should also find new mutants that cause C. elegans to live longer and we will use the accumulated knowledge of C. elegans ageing and E. coli metabolism to understand how these mutants work. We will combine mutants to see if we can make the animals live longer still. We will also use mutants of C. elegans that affect ageing to understand how the animal responds to changes caused by E. coli mutants. Together these studies reveal fundamental relationships between diet, lifespan and intestinal microbes. Our findings can be followed up in higher animals such as mice, hopefully leading to pharmaceutical and dietary interventions for humans both to slow ageing and decrease obesity. The results of this study will also stimulate discussion and help our understanding of a topic that concerns us all: What to eat to live to a healthy old age?

有很多证据表明，一般来说，饮食会影响衰老。饮食还会影响许多重大疾病，以改善人类健康为目标，生产膳食补充剂是一个数十亿美元的产业。人类饮食中有大量的成分，因此评估每种成分对衰老的影响是一项艰巨的任务。在实验动物身上研究衰老可以使实验更快、控制更好。秀丽隐杆线虫（Caenorhabditis elegans）是一种微小的线虫，寿命只有几周，是研究衰老生物学的成熟实验动物。通过破坏蠕虫体内的一些基因，蠕虫的寿命可以大大延长，其中一些基因与人类有明显的对应关系。例如，与人类对胰岛素产生反应所需的基因相似的基因被破坏，会导致蠕虫活得更长。在老鼠身上进行的实验表明，这一发现也适用于哺乳动物。动物的消化道中有许多微生物，主要是细菌，这些微生物在许多方面有助于营养。除了帮助吸收营养物质外，肠道细菌还会产生动物宿主无法产生的必需氨基酸和维生素等化合物。有人认为，肠道微生物的变化会导致肥胖。在实验室里，我们把秀丽隐杆线虫维持在一种活细菌上，这是一种无害的大肠杆菌，来自人类的肠道。这种菌株提供食物，但需要活着才能提供良好的营养。我们发现了一种变异的大肠杆菌，用它喂蠕虫可以使它们活得更久。我们发现，这种突变导致动物寿命延长的原因是叶酸合成的减少。所有细胞都需要叶酸，用于各种目的，尤其是细胞生长，但叶酸只在微生物和植物中产生，所以动物必须依靠它们的饮食。我们的实验表明，吃突变细菌的蠕虫的寿命延长了，因为它们比吃正常细菌的蠕虫摄入的叶酸少。此外，细菌缺乏叶酸来支持自身的新陈代谢，这一事实也有助于减缓以它们为食的蠕虫的衰老。我们还不知道减少的叶酸是如何导致这种效果的，但我们知道这并不是因为额外的叶酸是有毒的。大肠杆菌可能是被研究得最好的生物体，因为60多年来，它一直被用来了解细胞的基本运作和代谢。大肠杆菌大约有4000个基因，其中有3909个菌株，每个菌株中有一个基因被破坏。这项提议的目的是用这些突变株喂养蠕虫，寻找长寿的蠕虫和生长缓慢的蠕虫。我们希望能找到几种能延长蠕虫寿命和/或影响营养的大肠杆菌突变体。首先，我们应该找到破坏叶酸代谢相关基因的突变体。这些基因的特性将帮助我们了解叶酸的作用机制。其次，我们还应该找到新的突变体，使秀丽隐杆线虫活得更长，我们将利用积累的秀丽隐杆线虫衰老和大肠杆菌代谢的知识来了解这些突变体是如何工作的。我们将把突变体结合起来，看看能否让动物活得更久。我们还将使用影响衰老的秀丽隐杆线虫的突变体来了解动物如何对大肠杆菌突变体引起的变化作出反应。这些研究共同揭示了饮食、寿命和肠道微生物之间的基本关系。我们的发现可以在老鼠等高等动物中进行后续研究，希望能给人类带来药物和饮食干预，以减缓衰老和减少肥胖。这项研究的结果也将激发讨论，帮助我们理解一个与我们所有人有关的话题：吃什么才能健康地长寿？

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism.

DOI：
10.1016/j.cell.2013.02.035
发表时间：
2013-03-28
期刊：
Cell
影响因子：
64.5
作者：
Cabreiro F;Au C;Leung KY;Vergara-Irigaray N;Cochemé HM;Noori T;Weinkove D;Schuster E;Greene ND;Gems D
通讯作者：
Gems D

Excessive folate synthesis limits lifespan in the C. elegans: E. coli aging model.

DOI：
10.1186/1741-7007-10-67
发表时间：
2012-07-31
期刊：
BMC biology
影响因子：
5.4
作者：
Virk B;Correia G;Dixon DP;Feyst I;Jia J;Oberleitner N;Briggs Z;Hodge E;Edwards R;Ward J;Gems D;Weinkove D
通讯作者：
Weinkove D

A bacterial route for folic acid supplementation.